Researchers have found that the sirtuin SIRT1 stabilizes the human genome by suppressing retrotransposition, which occurs when parts of the genome transcribe themselves onto other parts.
When DNA modifies itself
Long interspersed elements-1 (LINE-1) have existed in organisms’ genomes, including our own, for well over a billion years [1]. They are the only autonomous elements that transpose themselves within the human genome, and they occupy a full sixth of it [2]. Two proteins generated by LINE-1 elements, ORF1 and ORF2, are responsible for a third of the human genome [1].
As catalysts of genomic instability, LINE-1 elements have aided in human evolution, and they are directly responsible for the complexity of the human brain [3]. However, this comes at a high cost: the same instability that allowed us to evolve is itself an aspect of aging, and it is directly responsible for multiple other aspects, including senescence [4] and cancer [5].
Heterochromatin is the packed non-coding DNA that functions as a transcriptional regulator. While it is well-known in aging research as a key part of epigenetic alterations [6], newer research has found that its age-related diminishment allows LINE-1 elements to proliferate [7]. H3K9me3, a fundamental marker of heterochromatin, has been found to be directly responsible for keeping LINE-1 elements in check [8].
A possible explanation for sirtuins’ effects
Sirtuins have been heavily researched in the context of aging. SIRT6 has been specifically identified as a suppressor of LINE-1 activity [9], and SIRT1 is known to have benefits against age-related disorders in several organisms, including in the lungs of mice [10]. However, before this study, no one had yet investigated whether or not SIRT1 suppresses LINE-1 as well.
In their first experiment, the researchers used HeLa cells, an established line of human cancer cells. Using fluorescent reporter proteins to identify LINE-1 activity, the researchers found that the overexpression of SIRT1 in these cells minimized this activity, and silencing SIRT1 increased it. Similar results were found in IMR90 human cells and mouse embryonic fibroblasts.
These results were due to direct effects on a LINE-1 internal promoter. Silencing SIRT1 increased the activity of this promoter, increasing the production of ORF2, which led to increased DNA damage within cells. Similarly, overexpressing SIRT1 decreased this damage. These results were confirmed with the DNA damage marker γH2AX.
Protection on multiple fronts
LINE-1 is also known to trigger the cGAS-STING inflammatory pathway [11], which often leads to cellular senescence. After a high dose of radiation exposure, the researchers found that 30% of a control group of HeLa cells became senescent; however, this dose was only sufficient to drive 13% of a SIRT1-overexpressing group into senescence. In HCA2-hTERT, another cell line, SIRT1 overexpression dropped senescence from 38% to 20% after a high radiation dose. Similarly, SIRT1 overexpression reduced the SASP factors secreted by senescent cells, while silencing SIRT1 increased them.
Quiescence is a state in which cells do not divide; however, unlike senescence, these cells are not incapable of division but are simply waiting for a trigger. SIRT1 was found to have exceptionally strong effects on LINE-1 in quiescent cells, being enriched at its loci and preventing it from harming these reserve cells.
The team then investigated how SIRT1 interacts with two well-known regulators of genomic stability, Lamin B1 and KAP1. Interestingly, while SIRT1 did not have any effects on the levels of these proteins, it improved their ability to interact, aiding in heterochromatin stability. SIRT1 was also found to be positively associated with H3K9me3 in chromatin.
While this research only involved cells and not mice or people, it offers plausible explanations for why SIRT1 has the effects reported in other studies. The researchers state that their “findings establish a new mechanistic framework for SIRT1-mediated senescence intervention, with profound implications for delaying aging and mitigating age-related diseases.” Further work will need to be done to confirm if this framework is correct and that these results hold true in vivo.
Literature
[1] Baldwin, E. T., van Eeuwen, T., Hoyos, D., Zalevsky, A., Tchesnokov, E. P., Sánchez, R., … & Taylor, M. S. (2024). Structures, functions and adaptations of the human LINE-1 ORF2 protein. Nature, 626(7997), 194-206.
[2] Beck, C. R., Collier, P., Macfarlane, C., Malig, M., Kidd, J. M., Eichler, E. E., … & Moran, J. V. (2010). LINE-1 retrotransposition activity in human genomes. Cell, 141(7), 1159-1170.
[3] Garza, R., Atacho, D. A., Adami, A., Gerdes, P., Vinod, M., Hsieh, P., … & Jakobsson, J. (2023). LINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification. Science Advances, 9(44), eadh9543.
[4] De Cecco, M., Criscione, S. W., Peckham, E. J., Hillenmeyer, S., Hamm, E. A., Manivannan, J., … & Sedivy, J. M. (2013). Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging cell, 12(2), 247-256.
[5] Rodić, N., & Burns, K. H. (2013). Long interspersed element–1 (LINE-1): passenger or driver in human neoplasms?. PLoS genetics, 9(3), e1003402.
[6] Lee, J. H., Kim, E. W., Croteau, D. L., & Bohr, V. A. (2020). Heterochromatin: an epigenetic point of view in aging. Experimental & molecular medicine, 52(9), 1466-1474.
[7] Li, X., Yu, H., Li, D., & Liu, N. (2024). LINE-1 transposable element renaissance in aging and age-related diseases. Ageing Research Reviews, 100, 102440.
[8] Guerra, M. V., Cáceres, M. I., Herrera-Soto, A., Arredondo, S. B., Varas-Godoy, M., van Zundert, B., & Varela-Nallar, L. (2022). H3K9 methyltransferases Suv39h1 and Suv39h2 control the differentiation of neural progenitor cells in the adult hippocampus. Frontiers in Cell and Developmental Biology, 9, 778345.
[9] Van Meter, M., Kashyap, M., Rezazadeh, S., Geneva, A. J., Morello, T. D., Seluanov, A., & Gorbunova, V. (2014). SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nature communications, 5(1), 5011.
[10] Zhou, J., Chen, H., Wang, Q., Chen, S., Wang, R., Wang, Z., … & Jin, J. (2022). Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription. Aging Cell, 21(8), e13680.
[11] Mathavarajah, S., & Dellaire, G. (2023). LINE-1: an emerging initiator of cGAS-STING signalling and inflammation that is dysregulated in disease. Biochemistry and Cell Biology, 102(1), 38-46.
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